Author(s): Ligen Lin 1, Keyun Chen 1, Waed Abdel Khalek 2, Jack Lee Ward 1, Henry Yang 1, Béatrice Chabi 2, Chantal Wrutniak-Cabello 2, Qiang Tong 1,3,*
Caloric restriction (CR) prolongs animal lifespan and delays the onset of age-related diseases , . In skeletal muscle, CR increases insulin sensitivity, modulates protein turnover and protects against the aging-related decline of mitochondrial activity and muscle function -. However, the molecular mechanism underlying the effects of CR in skeletal muscle is poorly understood.
The sirtuin family of genes has been proposed as possible mediators for the effects of CR. SIRT3, a sirtuin family member of NAD+ -dependent deacetylase, is the major mitochondrial protein deacetylase . SIRT3 expression is increased in response to fasting or caloric restriction -. SIRT3 deacetylates many mitochondrial enzymes to orchestrate metabolic alteration. For example, in the liver, SIRT3 deacetylates long-chain acyl CoA dehydrogenase (VCAD) to boost fatty acids [beta]-oxidation , 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) to increase ketogenesis , acetyl-CoA synthetase 2 (ACS2) to utilize acetate , , and ornithine transcarbamoylase (OTC) to detoxificate urea . SIRT3 also regulates mitochondrial electron transporta chain, such as complex I subunit NDUFA9 , complex II succinate dehydrogenase , and ATP synthase ATP5A . Furthermore, SIRT3 deacetylates MnSOD - and isocitrate dehydrogenase 2  to augment anti-oxidant action. SIRT3-deficient mice have greatly decreased levels of tissue adenosine triphosphate (ATP) , impaired cold tolerance when fasted , and more susceptibility to cardiac hypertrophy , , breast cancer  and high-fat diet-induced metabolic syndrome , .
The function of SIRT3 in skeletal muscle is not fully characterized. We have reported previously that caloric-restricted mice have increased SIRT3 expression in both white and brown adipose tissue  and skeletal muscle . We also found that the oxidative soleus muscle has higher SIRT3 expression than does glycolytic extensor digitorum longus or gastrocnemius muscles and that expression of SIRT3 in skeletal muscle is elevated by fasting and exercise training . Human studies revealed that muscle SIRT3 expression is down-regulated with age and up-regulated by endurance training . Conversely, sedentary elder human subjects have reduced muscle expression of SIRT3 and the peroxisome proliferator-activated receptor gamma coactivator-1[alpha] (PGC-1[alpha]), compared to young and active elder controls . SIRT3 deficiency leads to decreased muscle oxidative capacity and oxidative stress, resulting in defects of muscle insulin signaling .
AMPK is a ubiquitous heterotrimeric serine/threonine protein kinase, which functions as a fuel sensor in many tissues, including skeletal muscle . Activated AMPK stimulates ATP-generating catabolic pathways, such as fatty acid uptake and [beta]-oxidation by phosphorylating and inactivating acetyl-CoA carboxylase (ACC) . In addition, AMPK activation represses ATP-consuming processes, such as lipogenesis, protein synthesis and other biosynthetic pathways , . Activation of AMPK promotes a switch to type I fibers and increased exercise capacity , . In the muscle of SIRT3 knockout mice, we observed a down-regulation of AMPK phosphorylation .
Forkhead transcription factors are key components of the insulin/IGF signaling cascade, a conserved pathway regulating metabolism and aging . Nutrient deprivation, such...